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Pathology of the Heart in Friedreich's Ataxia: Review of the Literature and Report of One Case

G. SANCHEZ-CASIS, M. COTE AND A. BARBEAU

Quebec Cooperative Study of Friedreich's Ataxia

SUMMARY: A single case of typical Friedreich's ataxia was analyzed for cardiac changes and compared to the findings from the literature. Macro-scopically, there was a cardiomegaly with some degree of ventricular hyper­trophy and probable mild dilatation of the auricles. The more important and constant histologic changes were myo­cardial fibrosis and degeneration of the cardiac muscle cells. Granular deposits of calcium salts and iron were found in the muscle cells. A cardiomyopathy hypertrophic in type and occasionally obstructive appears to be an integral part of Friedreich's ataxia.

RESUME: Les modifications car-diaques trouvees dans le coeur d'un cas d'ataxie de Friedreich "typique" pre-alablement etudie sont analysees et comparees aux donnees de la litterature. Macroscopiquement, il y avail une car-dipmegalie avec un certain degre d' hypertrophic ventriculaire ainsi qu'une probable dilatation legere des auricules. Histologiquement, les change-ments les plus remarquables et con­stants etaient une fibrose du myocarde ainsi qu'une degenerescence des cellules musculaires cardiaques. Des depots granuleux de sets de calcium et de fer furent identifies dans ces cellules mus­culaires. En conclusion, une cardiomyo-pathie de type hypertrophique et parfois obstructive semble devoir etre une partie integrate de I'ataxie de Friedreich.

From the Centre Hospitaller Universitaire de Sherbrooke; and the Clinical Research Institute of Montreal.

Reprint requests for the complete supplement on Friedreich's ataxia to Dr. Andre Barbeau, Clinical Research Institute of Montreal, 110 Pine Avenue west, Montreal, Quebec, Canada H2W 1R7.

INTRODUCTION Friedreich (1861, 1863) described

the disease that bears his name. In the autopsy study of three cases, he found "myocardial damage" in two. It was not until 1887 that Pitt, in London, made the clinico-pathological correlation in patients with Friedreich's ataxia and heart disease.

In 1905, Lannois and Porrot, and, in 1933, Guizetti described 4 cases of extensive myocardial fibrosis and fatty degeneration and sclerosis of the coronary arteries without ob­struction. Nadas et al (1951) found similar changes in one case except for extensive obstruction of coro­nary arteries. Lorenz and col­laborators (1950) described myocar­dial hypertrophy and dilatation, slight irregularity and calcification of the aortic valve, and granular degen­eration and fibrosis of the myocar­dium with some "small cell" infiltra­tion. In 1952, Schilero et al gave a complete pathological and clinical description of common and uncom­mon cardiac changes. Common ones were similar to those described above, with the exception of specific round-cell infiltration with lympho­cytes and eosinophils. The uncom­mon ones were pericardial effusion, complete heart block or bundle-branch book, infiltration with mast cells, epicardial petechiae and hemorrhages, and fibrous pericardial thickening.

Hartman (1960) proposed a possi­ble pathogenic mechanism. The myocardial changes could be the re­sult of sympathetic overactivity sec­ondary to medullary lesions of the vagal nuclei. However, Thilenius and Grossman (1961) noted the his­

tological differences between the central nervous system and myocar­dial lesions. In 1962, Boyer et al reported 33 autopsy cases: 55% had myocardial alterations. The authors presented several theories about the pathogenesis. They stressed the possible role of scoliosis, a "neurogenic factor" , rheumatic fever, a congenital malformation, coronary artery occlusion or narrow­ing, and finally a single inborn error of metabolism expressing itself in both the central nervous system and the myocardium.

The same year, James and Fisch (1963) in one autopsy found a car­diomegaly and presented a complete study of the gross and microscopic findings. Many of these were similar to the ones described before, and others were non-specific. Among the findings of this report were the thorough study of coronary arteries and the changes in the other organs. However, many of these changes were not specific enough for a diffe­rential diagnosis from other pathologic entities. Finally, in the discussion, James and Fisch raised the possibility that involvement of the small arteries is responsible for the "myocarditis" in Friedreich's ataxia.

In 1964, Ivemark and Thoren noted in three autopsy cases, subin-timal fibrosis of the large and medium-size branches of the coro­nary arteries and subendocardial fib­roelastosis. They suggested an infec­tious or toxic etiology. In 1965, Soulie and collaborators reviewed 25 autopsy cases. The more important myocardial changes were the diffuse fibrosis and thickening of the media of the arterioles with microthrombi. In their own case, they described

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1973 R.B. 13-MAB-23

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Figure 1—Electrocardiogram two years prior to necropsy study showing atrial fibrillation with rapid ventricular rate and non-specific ST-T changes.

almost the same changes as in the literature.

Chelius et al, in 1967, studied a family of 4 afflicted siblings; three had clinically manifest heart in­volvement, and 2 developed dia­betes mellitus prior to death. The autopsy in 3 siblings showed cardiac changes similar to those previously described.

Hewer (1968) showed that over 50% of 82 patients died of cardiac complications, while nearly 75% had evidence of cardiac involvement during life. In 1970, Boehm et al described a case with hypertrophic subaortic stenosis. The microscopic alterations were again similar to the cases in the literature. Elias et al, in 1972, reported another case with hypertrophic subaortic stenosis. The same year, Tanaka et al (1972) de­scribed a case with extensive myocardial fibrosis and no changes in the spinal cord. Gach and co­authors (1971) published a case with

hypertrophic obstruct ive car­diomyopathy involving both ventri­cles.

In 1972, Olsen described the au­topsy findings in 3 cases, and Kron-grad and Joos (1972), an additional case of a 7 year old girl who had a paternal history of early death sec­ondary to myocardial infarction. They reported for the first time an elevation of the LDH isoenzyme-5 in a case of Friedreich's ataxia. Fi­nally, they stressed coronary artery disease and small-vessel occlusion as possible etiological factors and their relationship to the hyper-lipidemias and diabetes, both famil­ial disorders producing early diffuse coronary artery disease.

Ruschhaupt et al (1972) described another case associated with idiopathic hypertrophic subaortic stenosis and also stressed this kind of association, both disorders having a familial incidence. The same year, Harris and Nghiem (1972) published

an extensive study of car­diomyopathies and included the car­diomyopathies associated with generalized neurological or muscular diseases. They gave a thorough de­scription of the histopathology, especially the fibrosis of the conduc­tion system and sino-atrial node. Fi­nally, one of the more recent articles from Gabriel et al (1974) stated that in the majority of cases the car­diopathy of Friedreich's ataxia be­longs to the non-obstructive hyper­trophic cardiomyopathies.

CASE REPORT (RB-13-MAB-23) A 28 year old male Caucasian was

admitted at another hospital for ab­dominal and chest pains. He died 2 weeks later of renal failure. Only the heart, a few days after embalming, was available for the present nec­ropsy studies. The first symptoms of Friedreich's ataxia appeared at the age of 10. The neurological impair­ment progressed rapidly, and he had been confined to a wheel-chair since the age of 19. Two other siblings in this family of 9 children also suffered from Friedreich's ataxia.

Two years prior to his death, he was examined by one of us (M.C.). He presented few cardiovascular symptoms. He complained of slight shortness of breath after meals, al­though he was comfortable in the recumbent position. There was no

Figure 2—Artery of the atrioventricu­lar node without pathologic changes. (X63)

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nodes with few small areas of fibrosis. (X160)

Figure 4—A ganglion cell with granular degeneration in the epicardial fat, close to the sino-atrial node. (X160)

Figure 5—Microphotograph of a cross section of the anterior descending coronary artery to show intima thick­ening and an atheromatous plaque to the left. (X25)

history of frequent respiratory infec­tions. He had experienced episodes of palpitations in the previous two years and had been digitalized in­termittently. On physical examina­tion, he was non-cyanotic, slightly dyspneic, and moderately obese. B.P. 120/80. Heart rate irregular 110/min. There was no jugular ven­ous distension. The lungs were clear to auscultation. The chest was de­formed by a 60 degree dorsal scoliosis. Cardiac examination and auscultation revealed a slightly hyperactive right ventricle, and in­creased second pulmonic sound, and a protodiastolic third heart sound. No murmurs were heard. The elec­trocardiogram (Figure 1) showed atrial fibrillation with a rapid ventri­cular rate of 120 per minute, QRS axis of + 60° and non-specific ST-T changes. Cardiac catheterization re­vealed the following pressures: right atrium 6 mm Hg (mean), right ven­tricle 24/4 mm Hg, pulmonary artery 26/10, left ventricle 107/12 mm Hg, and aorta 108/92 mm Hg. There was no significant intraventricular sys­tolic pressure gradient at rest. The left ventricular and diastolic pres­sure was at the upper limit of nor­mal. The cardiac index was de­creased at 1.34 l/min./m2. The left ventricular angiogram revealed a dif­fusely hypokinetic and hyper-trophied left ventricle with an ejec­tion fraction of 49%. Myocardial metabolic studies were normal with no lactate production at rest and normal oxygen extraction. The oxy­hemoglobin dissociation curve was

Figure 6—High-power view of the artery to show the focal proliferation and sclerosis of the intima and the atheromatous plaque. (X160)

Figure 7—Median artery branch with no pathologic changes. (X63)

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normal. The patient was digitalized, and small doses of propanolol had to be added to maintain a controlled ventricular rate. The clinical and hemodynamic findings were compat­ible with a non-obstructive hyper­trophic cardiomyopathy. This pa­tient was hospitalized 3 months be­fore his death for the metabolic studies included in the protocol. Cardiac status was essentially the same as reported above.

Necropsy findings Only the heart, previously em­

balmed, was available for these studies. For this reason, some of the pathologic changes were interpreted in relation to the artifacts produced by that procedure. The neuropathology of the same patient will be reported in detail later. It showed the classical findings of Friedreich's ataxia with degenera­tion of the posterior roots, ganglia and dorsal columns, of the spino­cerebellar pathways and the pyrami­dal tracts. The gross pathology showed a cardiomegaly of 600 gm. with normal distribution of epicar-dial fat. The shape of the left ventri­cle was spherical. The left and right

auricles were dilated and there was a mild hypertrophy of both ventricles with decreased capacity of the left ventricle. The different measures were: pulmonary valve 6.0 cm., tricuspid valve 11.0 cm., aortic valve 6.0 cm., mitral valve 7.0 cm., left ventricle wall thickness 1.8 cm., and right ventricle 0.6 cm. The endocar­dium, myocardium, and epicardium were difficult to evaluate because of embalming changes. However, there were areas of whitish discoloration and congestion in the myocardium. Macroscopically, the coronary ar­teries had a normal architecture with a normal distribution.

The arteries of the atrioventricular (Figure 2) and sino-atrial node were dissected, and none showed micro­scopic changes. Sections of the atrio­ventricular node showed only mild fibrosis, mild nuclear changes, and some inflammatory cells (Figure 3). Sections of the sino-atrial node were normal. A group of ganglion cells and a nerve were found in the fatty tissue surrounding the sinus node. One of the ganglion cells showed granular degeneration, which could have been a post­mortem change (Figure 4). The rest of the conduction system showed no significant pathologic changes.

Figure 9—Infiltration of mononuclear cells, mainly lymphocytes. (X63)

Figure 10—Zone of degeneration with focal areas of calcification. (X63)

Generally, the coronary arteries showed few morphological changes, except for some focal proliferation of the intima, especially at the level of an atheromatous plaque (Figures 5 and 6). Microscopic examination of medium and small branches of the coronary arteries revealed no sig­nificant pathological changes (Figure 7).

Evidence of myocardial damage was diffuse and severe with intercel­lular fibrosis of irregular distribution affecting practically the whole car­diac muscle more pronounced in the left ventricle and septum (Figure 8).

Other changes, previously de­scribed, were also found such as infiltration by some lymphocytes and monocytic cells of the inter-stitium and the zones of fibrosis (Fig­ure 9). The only unusual findings were zones of cardiac muscle degen­eration with calcification that were well demonstrated with the Von Kossa stain (for calcium) (Figures 10, 11 and 12). However, Prussian-blue stains also showed the presence of iron pigment mixed in with the calcium. These zones of calcifica­tion were localized in the septum close to the conduction system (bundle of His).

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Figure II—High power of one of the areas of fibrosis, degenerat ion, and calcification. The special stain for iron was also posit ive. (X160)

Figure 12—Other high power to show the granular aspect and the intracellular deposi ts of calcium. (X160)

D I S C U S S I O N

After reviewing the literature, the more specific changes microscopi­cally were a cardiomegaly with some degree of ventricular hypertrophy and probable mild dilatation of the auricles.

Regarding the histologic changes, the more important and constant ones were myocardial fibrosis and degeneration of the cardiac muscle cells. The sclerotic changes of the coronary arteries and their branches, we believe, were non­specific. The changes were more de­generative, and, as in our case, there were atheromatous plaques involv­ing mainly the major branches of the coronary arteries, suggesting secon­dary myocardial damage and lending support to the hypothesis that the primary disease might predispose to early atherosclerosis. The distribu­tion and severity of the myocardial fibrosis and morphological changes are similar to previously described cases, being diffuse, but more pre­ponderant in the anterior wall of the left ventricle and septum.

The involvement of the septum atroventricular node, close to the His bundle and bundle branches, might explain in part the frequent abnormalities of the electrocardio­grams and vectocardiograms, such as QRS-axis deviation and right and left ventricular hypertrophy pat­terns. The conduction system does not, however, appear to be selec­tively involved.

The only findings not previously described in the literature are the granular deposits of calcium salts and iron in the muscle cells. Most likely, this is a dystrophic metabolic change secondary to cellular degen­eration and fibrosis, but its primary relationship to the disease cannot be ruled out. In idiopathic hypertrophic subaortic stenosis (IHSS) myocar­dial hypertrophy, similar morpholog­ical evidence of myocardial damage has been found. The disorderly ar­rangement of short muscle fibers characterizing this cardiomyopathy has not been found in this case or previously reported cases of Fried­reich's ataxia.

In conclusion, a cardiomyopathy,

hypertrophic in type and occasion­ally obstructive appears to be an integral part of Friedreich's ataxia. We think the pathological changes of the coronary vasculature can explain only in part the diffuse myocardial damage and hypertrophy. The most appealing hypothesis remains an un­identified genetically inherited in­born error, or errors, of metabolism as the etiology of the multiple sys­tem involvement in Friedreich's ataxia.

ACKNOWLEDGMENTS We express our gratitude to Dr. Sterling

Carpenter of the Montreal Neurological Insti­tute for having helped in making material available.

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